There is considerable evidence neurons that utilize the neuropeptide neurotensin (NT) are involved in both the mechanism of action of antipsychotic drugs (APDs) and the pathophysiology of schizophrenia. Despite this burgeoning database, there is no direct evidence to date that NT neurotransmission mediates behaviors relevant to the clinical efficacy of APDs. Conclusive demonstration of this association is the overall objective of this proposal. Hypotheses to be tested include the following; 1) Do all APDs increase NT release in the nucleus accumbens? 2) Is this increase in NT neurotransmission sufficient and necessary for the effects of APDs in behaviors relevant to clinical efficacy? 3) Are sex differences in schizophrenia related to ovarian hormone regulation of the NT system? 4) Are there specific alterations of the NT system in postmortem tissue consistent with an involvement of this system in the pathophysiology of schizophrenia? Thus, specific aim #1 scrutinizes the role of NT neurotransmission in animal models predictive of the clinical efficacy of APDs. Specific aim #2 evaluates the putative involvement of NT neurotransmission in the therapeutically relevant behavioral effects of chronically administered APDs. Two behavioral paradigms (latent inhibition and prepulse inhibition (PPI) of the acoustic startle reflex) with face, predictive and construct validity as animal models of sensorimotor gating in schizophrenia will be utilized. Specific aim #3 examines the behavioral consequence (specifically on sensorimotor gating ) of deficient NT neurotransmission in transgenic mice lacking NT. Specific aim #4 would correlate ovarian hormone regulation of NT neurotransmission (including NT gene expression, NT release, and the electrophysiologic responsiveness of nucleus accumbens neurons to NT) with estrous cycle regulation of sensorimotor gating. Specific aim # 5 explores a novel mechanism by which NT may directly modulate the D2 dopamine receptor. Specific aim #6 continues examination of NT neuronal systems in postmortem brain tissue from patients with schizophrenia, bipolar depression, or normal controls, with focus given to brain regions implicated in sensorimotor gating. This linkage of studies is intended to provide the first definitive evidence that intact NT neurotransmission is critically involved in behaviors relevant to the clinical efficacy of APDs, and provide clear rationale for the use of NT agonists as novel APDs.